PPAR? is a member of the nuclear receptor superfamily of ligand activated transcription factors. PPAR??has been implicated as a central regulator of adipogenesis. It was also elucidated as the receptor for the emerging class of anti-diabetic drugs known as thiazolidinedione, suggesting that it may function to curb the development of type II diabetes. We recently generated PPAR?-null mice. Embryos lacking both alleles of the gene die around day 10 of gestation. At this stage, the only organ expressing PPAR? is the placenta, suggesting that the mutant embryos die due to a deficiency in a structure of the PPAR?-dependent placental function. Nevertheless, the development, as well as the structure of the PPAR?-deficient placenta is grossly similar to that of wild-type placenta. This leads us to believe that the placental function under the control of PPAR? is probably metabolic rather than developmental. PPAR? functions a s heterodimeric complex with the RXR? nuclear receptor. Previous studies of RXR?-null mice detected a change in the structure of lipid droplets in the placenta. RXR??caters to a wide menu of heterodimeric partners, such as retinoic acid, thyroid hormone, vitamin D receptors and PPARs. Of those, given the known functions of PPAR? in lipid acquisition by adipose cells, it is conceivable that it might execute a similar function in the placenta. Therefore, the previously detected lipid droplet defect of RXR? null mice could be an attribute of its heterodimeric complex with PPAR?. Advanced microscopic methods will enable us to address this issue using PPAR? null placentas. RXR?-null mice die primarily due to a heart defect that involves, prior to the manifestation of a thin septum, precocious cardiomyocyte differentiation. There are several strong indications that this phenotype is non-autonomous. The early manifestations of this defect can be detected only by using high-resolution microscopic methods. It is therefore of great clinical significance to determine whether this phenotype can be recapitulated in the PPAR? nulls, since it could imply that the non-autonomous source of the heart defect stems from a deficiency in a PPAR? -dependent placental function. Moreover, it will establish a heretofore unknown linkage between the integrity of the placenta and heart development. We have recently begun these studies, which will first involve electron microscopic characterization of the placenta of wild-type and knockout mice and the structure of cardiomyocytes in embryonic normal and knock-out mice.